Human and murine major histocompatibility complex encoded class I molecules that are integrally involved in the recognition of virally infected cells by cytotoxic T lymphocytes (CTL) are isolated and their primary structure analyzed. The goal of these studies is to gain an understanding in molecular terms of their function and antigenic properties, as well as to obtain knowledge of their evolutionary relationships. In the case of human class I molecules, an HLA-A3 variant (E1) that is altered in its recognition by HLA-A3-influenza specific CTL has been analyzed. The altered functional properties of this variant were attributed to two amino acid substitutions that resulted from 3 base changes in the E1 gene. Analysis of the E1-gene product in murine fibroblasts after transfection demonstrated that human CTL can recognize human class I molecules on targets that do not express any other human gene product, and suggested that the effector T cell molecules T8 and LFA-1 are functionally involved in this recognition process. In the mouse studies have revealed a family of Ld-like molecules representing several distinct haplotypes and suggest that many D-region molecules have evolved from an Ld-like primordial gene. The fact that the H-2b haplotype Q10 class I gene encodes a soluble molecule was established by showing that L cells transformed with the gene secrete the predicted product. Class II molecules through their interaction with antigens are important for regulation of the antibody response by T-helper cells. Structural variations in IAk molecules involved in this regulatory process have been localized to the alpha1 and beta1 domains.